key: cord-0776858-ccitfd16 authors: Omarjee, Loukman; Janin, Anne; Perrot, Frédérique; Laviolle, Bruno; Meilhac, Olivier; Mahe, Guillaume title: Targeting T-cell senescence and cytokine storm with rapamycin to prevent severe progression in COVID-19 date: 2020-05-13 journal: Clin Immunol DOI: 10.1016/j.clim.2020.108464 sha: ccc42a3f3cba6843c01e90df718889255409e16f doc_id: 776858 cord_uid: ccitfd16 nan Loukman Omarjee, MD-PhD 1,2 , Anne Janin, MD-PhD 3 immunologists from China" [1] . We have read with great interest this review. As mentioned, current knowledge of anti-inflammation treatment in COVID-19 patients support the use of glucocorticoids, tocilizumab, JAK inhibitors, chloroquine and hydroxychloroquine [1] . The emergence of a new SARS-CoV-2 betacoronavirus has led to a major health-related crisis resulting in significant mortality in intensive care units (ICU), due to pulmonary complications of COVID-19 [1] . Mortality is also associated with advanced chronological age, diabetes, or cardiovascular disease [1] . Reduced counts and functional exhaustion of T lymphocytes, and cytokine release syndrome have been identified as adverse factors in patients affected by severe SARS-CoV-2 infection [2, 3] . Severe COVID-19 can therefore mimic a state of immune senescence [4] . The aim of this letter is to discuss the potentiality for rapamycin (sirolimus), an mTOR (mammalian target of rapamycin) inhibitor, to restore T-cell functionality and decrease cytokine storm. Cytokine storm, a hyper-inflammatory reaction in which cytokines are produced rapidly and extensively by immune cells in reaction to endogenous or exogenous stress [5] , is a major contributor to acute respiratory distress syndrome and multiple organ dysfunction syndrome [5] . In severe COVID-19 patients, IL-2, IL-6, IL-7, IL-10, TNF-α, G-CSF, IP-10, MCP-1, and MIP-1α levels increase significantly [1, 2] . Cytokine storm may promote T-cell apoptosis or necrosis, causing reduced T-cell counts [2] . T-cell senescence is a state of T-cell dysfunction that occurs in chronic infections and cancer [2, 4] . In COVID-19, patients over 60 years, and patients in ICU care have a decrease in CD4+, CD8+, and total T-cell numbers [2] , and this is inversely correlated with patients' survival [2] . T-cells play a vital role in viral clearance, particularly through secretion of perforin, granzyme and IFN-γ [3] . However, the expression of senescence markers PD-1 and Tim-3 [2] , CTLA-4 and TIGIT [3] is a hallmark of severe forms of COVID-19. In these patients, the potential of rapamycin to reverse T-cell senescence can be discussed [6] . In elderly with increased senescent PD-1+ T-cells, an analog of rapamycin enhanced immune function, and improved T-cell responses to antigenic stimulation with an acceptable risk/benefit balance [4] . In elderly with coronary artery disease, rapamycin reduced serum senescence markers through IL-6 suppression [7] . In patients infected with the H1N1 influenza virus, early adjuvant rapamycin therapy during a short period (2mg/day for 14 days) was significantly associated with an increased viral clearance, a greater improvement in lung injury (i.e. less hypoxemia), and a decrease of multiple organ dysfunction. The duration of ventilation in survivors was also shortened [8] . H1N1 and SARS-CoV-2 both activate mTOR, and NLRP3 inflammasome pathway [9, 10] leading to the production IL-1β, the mediator of lung inflammation, fever and fibrosis [8, 10] . Journal Pre-proof COVID-19, the binding of SARS-CoV-2 to Toll Like Receptor (TLR), which leads to IL-1β production, could be reversed by rapamycin [6] . In addition, rapamycin was recently identified in a bio-informatic drug study as a candidate for potential use in COVID-19 [6] . Each author has agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients Klickstein, mTOR inhibition improves immune function in the elderly HLH Across Speciality Collaboration, UK, COVID-19: consider cytokine storm syndromes and immunosuppression Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2 Effect of Low-Dose Rapamycin on Senescence Markers and Physical Functioning in Older Adults with Coronary Artery Disease: Results of a Pilot Study Adjuvant treatment with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in patients with severe H1N1 pneumonia and acute respiratory failure Delayed oseltamivir plus sirolimus treatment attenuates H1N1 virus-induced severe lung injury correlated with repressed NLRP3 inflammasome activation and inflammatory cell infiltration Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by COVID-19: anti-inflammatory strategies The authors wish to thank Ms Hazel Chaouch for English language correction. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. All authors declare they have nothing to disclose, and no competing interests. The authors do hereby declare that all illustrations and figures in the manuscript are entirely original and do not require reprint permission.